MICAL2is a novel human cancer gene controlling mesenchymal to epithelial transition involved in cancer growth and invasion

// Sara Mariotti 1, * , Ivana Barravecchia 1, * , Carla Vindigni 2 , Angela Pucci 3 , Michele Balsamo 1 , Rosaliana Libro 4 , Vera Senchenko 5 , Alexey Dmitriev 5 , Emanuela Jacchetti 6 , Marco Cecchini 6 , Franco Roviello 7 , Michele Lai 1, 8 , Vania Broccoli 9 , Massimiliano Andreazzoli 10 , Chiara M. Mazzanti 8 , Debora Angeloni 1 1 Institute of Life Sciences, Scuola Superiore Sant’Anna, 56124 Pisa, Italy 2 U.O.C. Anatomia Patologica, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, 53100 Siena, Italy 3 U.O.C. Anatomia Patologica, Azienda Ospedaliera Universitaria Pisana, 56100 Pisa, Italy 4 BIOS Doctoral School in Life Sciences, University of Pisa, 56124 Pisa, Italy 5 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia 6 NEST, National Enterprise for nanoScience and nanoTechnology, CNR and Scuola Normale Superiore, 56127 Pisa, Italy 7 Department of Human Pathology and Oncology, University of Siena, 53100 Siena, Italy 8 Pisa Science Foundation, 56100 Pisa, Italy 9 DIBIT H San Raffaele, 20132 Milan, Italy 10 Department of Biology, University of Pisa, 56127 Pisa, Italy * These authors contributed equally to this work Correspondence to: Debora Angeloni, e-mail: angeloni@sssup.it and angeloni@ifc.cnr.it Keywords: MICAL2, kidney cancer, gastric cancer, epythelial to mesenchymal transition, metastasis Received: April 24, 2015      Accepted: November 14, 2015      Published: December 12, 2015 ABSTRACT The MICAL (Molecules Interacting with CasL) proteins catalyze actin oxidation-reduction reactions destabilizing F-actin in cytoskeletal dynamics. Here we show for the first time that MICAL2 mRNA is significantly over-expressed in aggressive, poorly differentiated/undifferentiated, primary human epithelial cancers (gastric and renal). Immunohistochemistry showed MICAL2-positive cells on the cancer invasive front and in metastasizing cancer cells inside emboli, but not at sites of metastasis, suggesting MICAL2 expression was 'on' in a subpopulation of primary cancer cells seemingly detaching from the tissue of origin, enter emboli and travel to distant sites, and was turned 'off' upon homing at metastatic sites. In vitro , MICAL2 knock-down resulted in mesenchymal to epithelial transition, reduction of viability, and loss of motility and invasion properties of human cancer cells. Moreover, expression of MICAL2 cDNA in MICAL2-depleted cells induced epithelial to mesenchymal transition. Altogether our data indicate that MICAL2 over-expression is associated with cancer progression and metastatic disease. MICAL2 might be an important regulator of epithelial to mesenchymal transition and therefore a promising target for anti-metastatic therapy.